KU Leuven, Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium.
Expert Opin Ther Pat. 2012 Dec;22(12):1453-65. doi: 10.1517/13543776.2012.732571. Epub 2012 Oct 12.
Aminoacyl-tRNA synthetases (aaRSs) are one of the leading targets for development of antimicrobial agents. Although these enzymes are well conserved among prokaryotes, significant divergence has occurred between prokaryotic and eukaryotic aaRSs, which can be exploited in the discovery of broad-spectrum antibacterial agents. Although several aaRS inhibitors have been reported before, they failed as a result of poor selectivity and limited cell penetration.
This review covers January 2006 to April 2012 wherein several new analogues were claimed as aaRS inhibitors. Anacor Pharmaceuticals patented several boron-containing derivatives inhibiting the function of the editing domain of aaRSs. Two patents describe the combination of aaRS inhibitors with other antibacterial agents. Patents disclosing aaRS inhibitors for indications other than antimicrobial agents are not considered for review here.
Several recently disclosed leads may form the foundation for development of potent and selective bacterial aaRS inhibitors. In comparison with, for example, terbinafine and itraconazole, compound C10 (AN2690) is a very promising candidate for treatment of ungual and periungual infections with improved nail penetration and low keratin binding. In addition, Raplidyne, Inc. reported bicyclic heteroaromatic compounds as potent and selective inhibitors of bacterial MetRS. These have proven to be particularly effective for treatment of Clostridium difficile-associated diarrhea. Finally, combination of aaRS inhibitors to attenuate resistance looks as a viable strategy to expand the lifespan of existing antibiotics.
氨酰-tRNA 合成酶（aaRSs）是开发抗菌药物的主要靶标之一。尽管这些酶在原核生物中具有很好的保守性，但原核生物和真核生物的 aaRS 之间已经发生了显著的分化，这可以在广谱抗菌药物的发现中得到利用。尽管以前已经报道了几种 aaRS 抑制剂，但由于选择性差和细胞穿透能力有限，它们都失败了。
这篇综述涵盖了 2006 年 1 月至 2012 年 4 月期间，报道了几种新的类似物被认为是 aaRS 抑制剂。Anacor 制药公司申请了几项含有硼的衍生物专利，这些衍生物抑制 aaRSs 的编辑结构域的功能。有两项专利描述了 aaRS 抑制剂与其他抗菌剂的联合应用。这里不考虑披露 aaRS 抑制剂用于除抗菌剂以外适应症的专利。
最近披露的一些先导化合物可能为开发强效和选择性的细菌 aaRS 抑制剂奠定基础。与特比萘芬和伊曲康唑相比，化合物 C10（AN2690）是一种非常有前途的候选药物，可用于治疗指甲和甲周感染，具有改善的指甲穿透性和低角蛋白结合性。此外，RapIidyne, Inc. 报道了双环杂芳族化合物作为细菌 MetRS 的有效和选择性抑制剂。这些化合物已被证明对治疗艰难梭菌相关性腹泻特别有效。最后，aaRS 抑制剂的联合使用以减弱耐药性似乎是延长现有抗生素寿命的可行策略。
